AFREZZA (Page 2 of 7)

5.2 Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen

Glucose monitoring is essential for patients receiving insulin therapy. Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. These changes should be made under close medical supervision and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage modifications of concomitant oral antidiabetic treatment may be needed [see Drug Interactions (7.1, 7.2, and 7.3)].

5.3 Hypoglycemia

Glucose monitoring is essential for patients receiving insulin therapy. Hypoglycemia is the most common adverse reaction associated with insulins, including AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. AFREZZA has a distinct time action profile [see Clinical Pharmacology (12)] , which impacts the timing of hypoglycemia. Hypoglycemia can happen suddenly, and symptoms may differ across patients and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using certain medications [see Drug Interactions (7.4)] , or in patients who experience recurrent hypoglycemia.

Factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].

Risk Mitigation Strategies for Hypoglycemia

Patients and caregivers should be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.

5.4 Decline in Pulmonary Function

AFREZZA causes a decline in pulmonary function over time as measured by FEV1 . In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small [40 mL (95% CI: -80, -1)] but greater FEV1 decline than comparator-treated patients. The FEV1 decline was noted within the first 3 months, and persisted for the entire duration of therapy (up to 2 years of observation). In this population, the annual rate of FEV1 decline did not appear to worsen with increased duration of use. The effects of AFREZZA on pulmonary function for treatment duration longer than 2 years has not been established. There are insufficient data in long term studies to draw conclusions regarding reversal of the effect on FEV1 after discontinuation of AFREZZA. The observed changes in FEV1 were similar in patients with type 1 and type 2 diabetes.

Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms. In patients who have a decline of ≥ 20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent monitoring of pulmonary function in patients with pulmonary symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA [see Adverse Reactions (6)].

5.5 Lung Cancer

In clinical trials, two cases of lung cancer, one in controlled trials and one in uncontrolled trials (2 cases in 2,750 patient-years of exposure), were observed in patients exposed to AFREZZA while no cases of lung cancer were observed in patients exposed to comparators (0 cases in 2,169 patient-years of exposure). In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) occurred in non-smokers exposed to AFREZZA and were reported by investigators after clinical trial completion. These data are insufficient to determine whether AFREZZA has an effect on lung or respiratory tract tumors.

In patients with active lung cancer, a prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.

5.6 Diabetic Ketoacidosis

In clinical trials enrolling patients with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA in combination with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration.

5.7 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including AFREZZA.

If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. AFREZZA is contraindicated in patients who have had hypersensitivity reactions to AFREZZA or any of its excipients [see Contraindications (4)].

5.8 Hypokalemia

All insulin products, including AFREZZA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.

Monitor potassium levels in AFREZZA-treated patients at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations and patients receiving intravenously administered insulin).

5.9 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure.

Patients treated with insulin, including AFREZZA, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist should be considered.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Acute bronchospasm in patients with chronic lung disease [see Warnings and Precautions (5.1)]
  • Hypoglycemia [see Warnings and Precautions (5.3)]
  • Decline in pulmonary function [see Warnings and Precautions (5.4)]
  • Lung cancer [see Warnings and Precautions (5.5)]
  • Diabetic ketoacidosis [see Warnings and Precautions (5.6)]
  • Hypersensitivity reactions [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure of 3,017 patients to AFREZZA and include 1,026 patients with type 1 diabetes and 1,991 patients with type 2 diabetes. The mean exposure duration was 8.2 months for patients with type 1 diabetes and those with type 2 diabetes. In the overall population:

  • 1,874 patients were exposed to AFREZZA for 6 months and 724 patients for greater than one year.
  • 620 and 1,254 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for up to 6 months.
  • 238 and 486 patients with type 1 and type 2 diabetes, respectively, were exposed to AFREZZA for greater than one year (median exposure = 1.8 years).

AFREZZA was studied in placebo and active-controlled trials (n = 3 and n = 10, respectively).

The mean age of the population was 50.2 years and 20 patients were older than 75 years of age; 51% of the population were males; 83% were White, 5% were Black or African American, and 2% were Asian; 10% were Hispanic. At baseline, the type 1 diabetes population had diabetes for an average of 16.6 years and had a mean HbA1c of 8.3%, and the type 2 diabetes population had diabetes for an average of 10.7 years and had a mean HbA1c of 8.8%. At baseline, 33% of the population reported peripheral neuropathy, 32% reported retinopathy and 20% had a history of cardiovascular disease.

Table 1 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of controlled trials in type 2 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on placebo and/or comparator and occurred in at least 2% of patients treated with AFREZZA.

Table 1. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 2 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA

*Carrier particle without insulin was used as placebo [see Description (11.1)].

AFREZZA (n = 1,991) Placebo* (n = 290) Non-placebo comparators (n=1,363)
Cough 25.6%4.4%3.1%2.7%2.2%2.0%2.0% 19.7%3.8%2.8%1.4%1.0%0.7%0.3% 5.4%0.9%1.8%2.2%0.9%0.6%1.0%
Throat pain or irritation
Headache
Diarrhea
Productive cough
Fatigue
Nausea

Table 2 shows the frequency of common adverse reactions, excluding hypoglycemia, associated with the use of AFREZZA in the pool of active-controlled trials in type 1 diabetes patients. These adverse reactions were not present at baseline, occurred more commonly on AFREZZA than on comparator, and occurred in at least 2% of patients treated with AFREZZA.

Table 2. Common Adverse Reactions That Occurred in ≥ 2% in Patients with Type 1 Diabetes Mellitus (excluding Hypoglycemia) Treated with AFREZZA
AFREZZA(n=1026) Subcutaneous Insulin (n = 835)
Cough 29.4% 4.9%
Throat pain or irritation 5.5% 1.9%
Headache 4.7% 2.8%
Pulmonary function test decreased 2.8% 1.0%
Bronchitis 2.5% 2.0%
Urinary tract infection 2.3% 1.9%

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including AFREZZA [see Warnings and Precautions (5.3)]. The incidence of severe and non-severe hypoglycemia in AFREZZA-treated patients versus placebo-treated patients with type 2 diabetes is shown in Table 3. A hypoglycemic episode was recorded if a patient reported symptoms of hypoglycemia with or without a blood glucose value consistent with hypoglycemia. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either a blood glucose value consistent with hypoglycemia or prompt recovery after treatment for hypoglycemia.

Table 3. Incidence of Severe and Non-Severe Hypoglycemia in a Placebo-Controlled Study of Patients with Type 2 Diabetes
AFREZZA (N=177) Placebo (N=176)
Severe Hypoglycemia 5.1% 1.7%
Non-Severe Hypoglycemia 67% 30%

Cough

Approximately 27% of patients treated with AFREZZA reported cough, compared to approximately 5% of patients treated with comparator. In clinical trials, cough was the most common reason for discontinuation of AFREZZA therapy (3% of AFREZZA-treated patients).

Pulmonary Function Decline

In clinical trials lasting up to 2 years, excluding patients with chronic lung disease, patients treated with AFREZZA had a 40 mL (95% CI: -80, -1) greater decline from baseline in forced expiratory volume in one second (FEV1 ) compared to patients treated with comparator anti-diabetes treatments. The decline occurred during the first 3 months of therapy and persisted over 2 years (Figure 2). A decline in FEV1 of ≥ 15% occurred in 6% of AFREZZA-treated patients compared to 3% of comparator-treated patients [see Warnings and Precautions (5.4)].

Figure 2. Mean (+/-SE) Change in FEV 1 (Liters) from Baseline for Type 1 and Type 2 Diabetes Patients

Figure 2
(click image for full-size original)

Weight Gain

Weight gain has occurred with some insulin therapies, including AFREZZA. Weight gain has been attributed to the anabolic effects of insulin and the decrease in glycosuria. In a clinical trial of patients with type 2 diabetes [see Clinical Studies (14.3)] , there was a mean 0.49 kg weight gain among AFREZZA-treated patients compared with a mean 1.13 kg weight loss among placebo-treated patients.

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